MM responds well to initial chemotherapy but relapses occur in the majority of MM patients and nearly all patients die from progressive disease within 6 years. We hypothesize that targeted nanotherapy will disrupt the transformative influence of cMyc on myeloma progression and significantly impact on the care and extend survival of MM patients. This proposal, invokes a targeted therapeutic nanoparticle approach to deliver potent payloads of c-Myc-Max dimerization inhibitors specifically to myeloma cells in marrow while minimizing off- target toxicities. Myc encodes a helix-loop-helix transcription factor upregulated in 50-80% of human cancers that is associated with 100,000 US cancer deaths per year. Myc heterodimerizes with its partner Max to control target gene transcription and is deeply integrated into the regulatory and control mechanisms governing cell viability and proliferation. We and others have used animal models to demonstrate the cancer-inducing properties of Myc as well as a dependence of the transformed phenotype on continued expression of Myc, a phenomenon known as oncogene addiction. The loss of Myc proteins inhibits cell proliferation and growth, accelerates differentiation, increases cell adhesion, and accentuates the response to DNA damage. MYC activates transcription and represses target gene expression through Miz-1 transcription factor or by the regulation of micro-RNAs (miRs). However, rather than initiating a specific transcriptional program, MYC amplifies the output of existing transcriptional programs within a given cell. Myc is expressed by normal and cancer cells, but the former are generally quiescent with minimal Myc expression. Myc's increased expression in cancer has long made it an important but elusive target for anti-cancer therapeutics, particularly in MM, which is highly susceptible to Myc-Max interference. Unfortunately, several effective small-molecule inhibitors of the MYC-MAX interaction in vitro failed when applied in vivo due to rapid systemic metabolism, poor bioavailability, and an inability to achieve effective drug levels in tumors. We have demonstrated substantially increased survival in an aggressive metastatic mouse model of MM by delivering Myc-Max dimerization antagonists as Sn 2 lipase labile prodrugs (MI1-PD) using a novel lipid-micellar nanotherapeutic targeted to the VLA-4 integrin (?4?1) receptor. The overarching aim of this program will be to select and develop a transformative and clinically translatable VLA-4 targeted cMyc-Max antagonist PD nanotherapeutic candidate to maximize MM survival. The specific aims of this translational project are: Aim 1: Design, synthesize, develop, characterize and evaluate novel VLA-4 targeted Sn 2 lipase-labile cMyc- Max inhibitor prodrug nanotherapies. Selected small molecule cMyc-Max inhibitors that increase intracellular drug retention or bind differentially to cMyc to antagonize dimerization will be synthesized into Sn 2 prodrugs, characterized analytically, and studied physicochemically and biologically as nanotherapeutics to define in vitro potency, nanoparticle stability, and in vivo toxicity, pharmacokinetics and biodistribution pharmacology. Aim 2: Demonstrate optimized survival in preclinical mouse models of MM using VLA-4 Sn 2 cMyc-prodrug nanotherapy and assess the basis for noncurative responses. The efficacy of VLA-4 Sn 2 cMyc-prodrug nanotherapies will be compared and selected based on survival, noninvasive imaging, and clinical biomarkers of disseminated MM in two separate preclinical models: 5TGM1/KaLwRij. We anticipate anti-Myc nanoparticles used as a single agent will prolonging survival, but most animals will eventually succumb to MM. MM clones from mice relapsing following treatment will be characterized using flow cytometry, RNA and DNA sequencing to determine the basis of therapeutic resistance and potential susceptibility to complementary treatments. Aim 3. Establish combinations of VLA-4-cMyc-PD nanotherapy with standard-of-care therapies to increase MM sensitivity to cMyc-antagonism and to address MM surviving clonal populations following Myc-PD nanotherapy. The efficacy of VLA-4 Sn 2 cMyc-prodrug nanotherapies used in combination with currently approved chemotherapies will be compared and selected based on clinical biomarkers, noninvasive imaging, and survival in preclinical animal models of MM. First, traditional chemotherapies will be dosed intravenously in combination with VLA-4 Sn 2 cMyc-prodrug nanotherapies.